Objective:
To investigate the efficacy of rituximab as rescue therapy in patients with relapsing-remitting multiple sclerosis (RRMS) and persistent disease activity confirmed by magnetic resonance ...imaging (MRI) despite immunosuppressive disease-modifying therapy (DMT).
Methods:
In this observational nationwide retrospective multicenter study, we first identified 351 off-label rituximab-treated patients through a cohort of 15,984 RRMS patients. In this group, we identified patients with disease activity prior to rituximab confirmed by MRI (one or more new T2 lesion and/or gadolinium-enhancing lesion) despite immunosuppressive DMT (fingolimod, natalizumab, or mitoxantrone) with a follow-up after rituximab initiation longer than 6 months. Outcome data were collected from the French Observatory of Multiple Sclerosis (OFSEP) register and medical charts.
Results:
A total of 50 patients were identified. Median rituximab treatment duration was 1.1 (0.5–6.4) year. Mean annualized relapse rate significantly decreased from 0.8 during last immunosuppressive DMT to 0.18 after rituximab (p < 0.0001). While 72% of patients showed gadolinium-enhancing lesions on the last MRI performed during last immunosuppressive DMT, 8% of them showed gadolinium-enhancing lesions on the first MRI performed 6.1 (range 1.4–18.4) months after rituximab (p < 0.0001).
Conclusion:
This study provides level IV evidence that rituximab reduces clinical and MRI disease activity in patients with active RRMS despite immunosuppressive DMT.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
Abstract Background No drug has been found to have any impact on progressive multiple sclerosis (MS). Biotin is a vitamin acting as a coenzyme for carboxylases involved in key steps of energy ...metabolism and fatty acids synthesis. Among others, biotin activates acetylCoA carboxylase, a potentially rate-limiting enzyme in myelin synthesis. Objectives The aim of this pilot study is to assess the clinical efficacy and safety of high doses of biotin in patients suffering from progressive MS. Study design Uncontrolled, non-blinded proof of concept study Methods 23 consecutive patients with primary and secondary progressive MS originated from three different French MS reference centers were treated with high doses of biotin (100–300 mg/day) from 2 to 36 months (mean=9.2 months). Judgement criteria varied according to clinical presentations and included quantitative and qualitative measures. Results In four patients with prominent visual impairment related to optic nerve injury, visual acuity improved significantly. Visual evoked potentials in two patients exhibited progressive reappearance of P100 waves, with normalization of latencies in one case. Proton magnetic resonance spectroscopy (H-MRS) in one case showed a progressive normalization of the Choline/Creatine ratio. One patient with left homonymous hemianopia kept on improving from 2 to 16 months following treatment׳s onset. Sixteen patients out of 18 (89%) with prominent spinal cord involvement were considered as improved as confirmed by blinded review of videotaped clinical examination in 9 cases. In all cases improvement was delayed from 2 to 8 months following treatment׳s onset. Conclusions These preliminary data suggest that high doses of biotin might have an impact on disability and progression in progressive MS. Two double-blind placebo-controlled trials are on going.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
An 87-year-old man presented with a 2-day history of painful bilateral visual loss. On examination, exophthalmos, lid edema, chemosis, and optic disc edema, on the left side only, were found. Visual ...acuity was 4/10 OD and no light perception OS. Magnetic resonance imaging (MRI) revealed bilateral optic neuritis and a diffuse and severe infiltration of the intra- and extraconal fat on the left. Laboratory testing was negative except for serum myelin oligodendrocyte glycoprotein (MOG) antibodies. This presentation adds a new variant to the MOG-associated disease spectrum. Testing for MOG antibodies should be considered in patients presenting with diffuse orbital inflammation and optic neuritis.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
Viruses disrupt the host cell microRNA (miRNA) network to facilitate their replication. Human T-cell leukemia virus type I (HTLV-1) replication relies on the clonal expansion of its host CD4(+) and ...CD8(+) T cells, yet this virus causes adult T-cell leukemia/lymphoma (ATLL) that typically has a CD4(+) phenotype. The viral oncoprotein Tax, which is rarely expressed in ATLL cells, has long been recognized for its involvement in tumor initiation by promoting cell proliferation, genetic instability, and miRNA dysregulation. Meanwhile, HBZ is expressed in both untransformed infected cells and ATLL cells and is involved in sustaining cell proliferation and silencing virus expression. Here, we show that an HBZ-miRNA axis promotes cell proliferation and genetic instability, as indicated by comet assays that showed increased numbers of DNA-strand breaks. Expression profiling of miRNA revealed that infected CD4(+) cells, but not CD8(+) T cells, overexpressed oncogenic miRNAs, including miR17 and miR21. HBZ activated these miRNAs via a posttranscriptional mechanism. These effects were alleviated by knocking down miR21 or miR17 and by ectopic expression of OBFC2A, a DNA-damage factor that is downregulated by miR17 and miR21 in HTLV-1-infected CD4(+) T cells. These findings extend the oncogenic potential of HBZ and suggest that viral expression might be involved in the remarkable genetic instability of ATLL cells.
Background:
A paradoxical discrepancy between severe peripapillary retinal nerve fiber layer (pRNFL) atrophy and good visual outcome had been reported in patients with myelin oligodendrocyte ...glycoprotein-immunoglobulin G (MOG-IgG)-associated optic neuritis (ON). However, only visual acuity (VA) was assessed.
Objectives:
To study visual field (VF) outcomes of patients with MOG-IgG-associated ON and evaluate the correlation between functional eye outcome and retinal structural changes assessed by optical coherence tomography.
Methods:
The records of 32 patients with MOG-IgG-associated ON who underwent ophthalmological examination at least 12 months after ON onset were reviewed. Degree of VF disability was determined by mean deviation (MD).
Results:
At final assessment (median, 35 months), 4.2% of 48 affected eyes (AE) had VA ⩽ 0.1, 40% had abnormal MD, and among AE with final VA ⩾ 1.0, 31% had mild to moderate damage. Thinning of the inner retinal layers was significantly correlated with MD impairment. Analysis demonstrated a threshold of pRNFL thickness (50 µm), below which MD was significantly worse (mean, −2.27 dB vs −17.72 dB; p = 0.0003). ON relapse was significantly associated with poor visual outcome assessed by MD.
Conclusion:
Functional impairment measured with VF is not rare, and MD assessment better reflects actual structural damage.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
To compare 3D-Fast Gray Matter Acquisition with Phase Sensitive Inversion Recovery (3D-FGAPSIR) with conventional 3D-Short-Tau Inversion Recovery (3D-STIR) and sagittal T1-and T2-weighted MRI dataset ...at 3 Tesla when detecting MS spinal cord lesions.
This prospective single-center study was approved by an institutional review board and enrolled participants from December 2016 to August 2018. Two neuroradiologists blinded to all data, individually analyzed the 3D-FGAPSIR and the conventional datasets separately and in random order. Discrepancies were resolved by consensus by a third neuroradiologist. The primary judgment criterion was the number of MS spinal cord lesions. Secondary judgment criteria included lesion enhancement, lesion delineation, reader-reported confidence and lesion-to-cord-contrast-ratio. A Wilcoxon's test was used to compare the two datasets.
51 participants were included. 3D-FGAPSIR detected significantly more lesions than the conventional dataset (344 versus 171 respectively, p<0.001). Two participants had no detected lesion on the conventional dataset, whereas 3D-FGAPSIR detected at least one lesion. 3/51 participants had a single enhancing lesion detected by both datasets. Lesion delineation and reader-reported confidence were significantly higher with 3D-FGAPSIR: 4.5 (IQR 1) versus 2 (IQR 0.5), p<0.0001 and 4.5 (IQR 1) versus 2.5 (IQR 0.5), p<0.0001. Lesion-to-cord-contrast-ratio was significantly higher using 3D-FGAPSIR as opposed to 3D-STIR and T2: 1.4 (IQR 0,3) versus 0.4 (IQR 0,1) and 0.3 (IQR 0,1)(p = 0.04). Correlations with clinical data and inter- and intra-observer agreements were higher with 3D-FGAPSIR.
3D-FGAPSIR improved overall MS spinal cord lesion detection as compared to conventional set and detected all enhancing lesions.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background:
In relapsing-remitting multiple sclerosis (RRMS), early identification of suboptimal responders can prevent disability progression.
Objective:
We aimed to develop and validate a dynamic ...score to guide the early decision to switch from first- to second-line therapy.
Methods:
Using time-dependent propensity scores (PS) from a French cohort of 12,823 patients with RRMS, we constructed one training and two validation PS-matched cohorts to compare the switched patients to second-line treatment and the maintained patients. We used a frailty Cox model for predicting individual hazard ratios (iHRs).
Results:
From the validation PS-matched cohort of 348 independent patients with iHR ⩽ 0.69, we reported the 5-year relapse-free survival at 0.14 (95% confidence interval (CI) 0.09–0.22) for the waiting group and 0.40 (95% CI 0.32–0.51) for the switched group. From the validation PS-matched cohort of 518 independent patients with iHR > 0.69, these values were 0.37 (95% CI 0.30–0.46) and 0.44 (95% CI 0.37–0.52), respectively.
Conclusions:
By using the proposed dynamic score, we estimated that at least one-third of patients could benefit from an earlier switch to prevent relapse.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
Background
Chronic visual loss is a disabling feature in patients with multiple sclerosis (MS). It was recently shown that MD1003 (high-dose pharmaceutical-grade biotin or hdPB) may improve ...disability in patients with progressive MS.
Objective
The aim of this study was to evaluate whether MD1003 improves vision compared with placebo in MS patients with chronic visual loss.
Methods
The MS-ON was a 6-month, randomized, double-blind, placebo-controlled study with a 6-month open-label extension phase. Adult patients with MS-related chronic visual loss of at least one eye visual acuity (VA) below 0.5 decimal chart were randomized 2:1 to oral MD1003 300 mg/day or placebo. The selected eye had to show worsening of VA within the past 3 years following either acute optic neuritis (AON) or slowly progressive optic neuropathy (PON). The primary endpoint was the mean change from baseline to month 6 in VA measured in logarithm of the minimum angle of resolution (logMAR) at 100% contrast of the selected eye. Visually evoked potentials, visual field, retinal nerve fiber layer (RNFL) thickness, and health outcomes were also assessed.
Results
Ninety-three patients received MD1003 (
n
= 65) or placebo (
n
= 28). The study did not meet its primary endpoint, as the mean change in the primary endpoint was nonsignificantly larger (
p
= 0.66) with MD1003 (− 0.061 logMAR, + 3.1 letters) than with placebo (− 0.036 logMAR, + 1.8 letters). Pre-planned subgroup analyses showed that 100% contrast VA improved by a mean of + 2.8 letters (− 0.058 logMAR) with MD1003 and worsened by − 1.5 letters (+ 0.029 logMAR) with placebo (
p
= 0.45) in the subgroup of patients with PON. MD1003-treated patients also had nonsignificant improvement in logMAR at 5% contrast and in RNFL thickness and health outcome scores when compared with placebo-treated patients. There was no superiority of MD1003 vs placebo in patients with AON. The safety profile of MD1003 was similar to that of placebo.
Conclusions
MD1003 did not significantly improve VA compared with placebo in patients with MS experiencing chronic visual loss. An interesting trend favoring MD1003 was observed in the subgroup of patients with PON. Treatment was overall well tolerated.
Trial registration
EudraCT identifier 2013-002112-27. ClinicalTrials.gov Identifier: NCT02220244
Funding
MedDay Pharmaceuticals.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Extracellular vesicles (EVs) can participate in intercellular communication and pathogenesis. EVs contain many cargos, including proteins, and the composition of EVs differs between cell-types and ...activation levels. Thus, plasma EVs can be used as a biomarker of systemic response to infection and/or disease progression. In this study, we aimed at describing alterations in the protein content of plasma EVs upon infection with the human T-lymphotropic retrovirus type 1 (HTLV-1). HTLV-1 is the etiological agent of a lymphoproliferative disease (ATL) and a series of inflammatory diseases, including a neurodegenerative inflammatory disease (HAM/TSP). We found that plasma EVs are more abundant and smaller in HTLV-1 asymptomatic carriers or HAM/TSP patients when compared to uninfected healthy donors. Moreover, EVs from HTLV-1 infected donors contain markers of metabolic and mitochondrial stress.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
HTLV-1 is the causative agent of a severe form of adult T cell leukemia/Lymphoma (ATL), and of a chronic progressive neuromyelopathy designated HTLV-1 associated myelopathy/tropical spastic ...paraparesis (HAM/TSP). Two important HTLV-1-encoded proteins, Tax-1 and HBZ, play crucial roles in the generation and maintenance of the oncogenic process. Less information is instead available on the molecular and cellular mechanisms leading to HAM/TSP. More importantly, no single specific biomarker has been described that unambiguously define the status of HAM/TSP. Here we report for the first time the finding that HBZ, described until now as an exclusive nuclear protein both in chronically infected and in ATL cells, is instead exclusively localized in the cytoplasm of peripheral blood mononuclear cells (PBMC) from patients suffering of HAM/TSP. Interestingly, at the single cell level, HBZ and Tax-1 proteins are never found co-expressed in the same cell, suggesting the existence of mechanisms of expression uncoupling of these two important HTLV-1 viral products in HAM/TSP patients. Cells expressing cytoplasmic HBZ were almost exclusively found in the CD4+ T cell compartment that was not, at least in a representative HAM/TSP patient, expressing the CD25 marker. Less than 1 percent CD8+ T cells were fond positive for HBZ, while B cells and NK cells were found negative for HBZ in HAM/TSP patients. Our results identify the cytoplasmic localization of HBZ in HAM/TSP patient as a possible biomarker of this rather neglected tropical disease, and raise important hypotheses on the role of HBZ in the pathogenesis of the neuromyelopathy associated to HTLV-1 infection.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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